1. Field of the Invention
This invention relates to a second medical use of thiazolidine compounds having anti-diabetic properties. These compounds are also of use for the control of essential hypertension.
Hypertension of unknown etiology is termed essential hypertension. A relatively common disease state in people, this disease has been associated with the early onset of coronary disease, kidney failure and stroke. Essential hypertension is generally asymptomatic and has been termed a silent killer. It is believed to affect 60 million people in the United States.
Current pharmaceutical treatments for essential hypertension include diuretics, beta-blockers, angiotensin converting enzyme inhibitors and calcium antagonists. Currently available anti-hypertensive agents are not without side effects such as the elevation of blood lipids and glucose. The elevation of blood lipids and glucose by these agents has been suggested as a reason why anti-hypertensive agents have not demonstrated any benefit to patients being monitored in death rate studies.
While not wishing to be bound by theory, insulin levels are known to be high in individuals with hypertension. The association of carbohydrate metabolic abnormalities with hypertension has been suggested. There has been significant debate on the cause of essential hypertension, the mechanism and role of insulin or high levels of glucose on hypertension.
To date a causal relationship between insulin levels and hypertension has not been established. The biological mechanism of the pharmaceutical effects of the thiazolidine compounds of use in this invention is unknown. They are known to lower insulin, but the nature of this observation is unknown. It is unclear whether the insulin reduction associated with these drugs is directly or indirectly related to pancreas secretion, the peripheral cells or both.
To our knowledge no one has demonstrated a lowering of hypertension in non-obese, non-diabetic individuals by treatment with insulin lowering drug therapy. The discovery of a new use for this widely studied class of drugs will provide a new therapeutic approach for essential hypertension.
2. Information Disclosure
The compounds which comprise the pharmaceuticals of this invention are known as anti-diabetic compounds which lower the concentration of glucose and lipids in blood. Representative compounds comprise U.S. Pat. Nos. 4,812,570, 4,775,687, 4,725,610, 4,582,839, 4,572,912, 4,486,594, 4,461,902, 4,444,779 and European Pat. No. 0277,836.
Thiazolidine compounds unrelated to those described herein have been described as anti-hypertensive agents. Japan No. 56071081.
A number of references have documented the association of insulin and glucose concentration with blood pressure. The rat has been a laboratory model for documenting this association. Kurtz, T. W. et al., 1989, The Zucker Fatty Rat as a Genetic Model of Obesity and Hypertension, Hypertension, 13:896-901; Reaven, G. M., 1988, Attenuation of Fructose-induced Hypertension in Rats by Exercise Training, Hypertension, 12:129-132; Mondon C. E. and Reaven, G. M., 1988, Preliminary Report: Evidence of Abnormalities of Insulin Metabolism in Rats with Spontaneous Hypertension. Metabolism 37:303-305 and Hwang, I, et al., 1987, Fructose-Induced Insulin Resistance and Hypertension in Rats, Hypertension, 10:512-516.
In humans, the following references have suggested hyperinsulinemia as a factor in essential hypertension. Insulin resistance, which is thought to be the impaired ability of peripheral cells to respond to insulin and thus fail to increase their uptake of glucose from blood, has been associated with non-obese, non-diabetic persons having essential hypertension. Tedde, R., et al., 1989, Antihypertensive Effect of Insulin Reduction in Diabetic-Hypertensive Patients, Amer. J. Hypertension, 2:163-170; Hall, J. E., et al., 1989, Does Chronic Hyperinsulinemia Cause Hypertension?, Amer. J. Hypertension, 2:171-173; Zavaroni, I, et al., 1989, Risk Factors for Coronary Artery Disease in Healthy Persons with Hyperinsulinemia and Normal Glucose Tolerance, N. Eng. J. Med. 320:702-706; Ferrannini, E., et al., 1987, Insulin Resistance in Essential Hypertension, N. Eng. J. Med., 317:350-357; Fuh, M., et al., 1987, Abnormalities of Carbohydrate and Lipid Metabolism in Patients with Hypertension, Arch Intern. Med. 147:1035-1038; Reaven, G. M. and Hoffman, B. B., 1987, Occasional Survey: A Role for Insulin in the Aetiology and Course of Hypertension?, Lancet, Aug. 22, 1987 pages 435-436; Zavaroni, I. et al., 1987, Evidence that Multiple Risk Factors for Coronary Artery Disease Exist in Persons with Abnormal Glucose Tolerance, Amer. J. Med. 83: 609-612. This association was first recognized in obese persons with hypertension. Manicardi, V., 1986, Evidence for an Association of High Blood Pressure and Hyperinsulinemia in Obese Man, J. Clin. Endocrin. Metab. 62:1302-1304; Lucas, C. P. et al., 1985, Insulin and Blood Pressure in Obesity, Hypertension, 7:702-706; and Dustan, H. P. Mechanisms of Hypertension Associated with Obesity, Ann Intern. Med. 98:860-864.
Insulin resistance in man has been associated with a newly defined disease syndrome which includes hypertension. Reaven, G. M. and Hoffman, B. B., 1988, Hypertension: A Disease of Carbohydrate and Lipoprotein Metabolism, The Kidney 20:19-23; and, Foster, D. W., 1989, Insulin Resistance - A Secret Killer?, New Eng. J. Med. 320:733-734, and Reaven, G. M., 1988, Banting Lecture: Role of Insulin Resistance in Human Disease, Diabetes 37:1595-1607.
The thiazolidine compound used to demonstrate the antihypertensive activity of thiazolidine compounds was Ciglitazone. Ciglitazone is a known anti-diabetic agent. Colca, J. R., et al., 1988, Ciglitazone, A Hypoglycemic Agent: Early Effects on the Pancreatic Islets of Ob/Ob Mice, Metabolism, 37:276-280; and, Chang, A. Y., et al., 1983, Ciglitazone, A New Hypoglycemic Agent, Diabetes 32:830-838.
The mechanism whereby insulin might affect blood pressure is a topic of controversy in the medical and scientific communities. The prevailing theory is that insulin plays an important role in sodium metabolism. Rocchini, A. P. et al., 1989, The Effect of Weight Loss on the Sensitivity of Blood Pressure to Sodium in Obese Adolescents, New Eng. J. of Med. 321:580-585 and DeFronzo, R. A., 1981, The Effect of Insulin on Renal Sodium Metabolism, Diabetologia, 21:165-171. The inventors of the subject invention are major proponents of a less accepted counter theory suggesting calcium metabolism is a major part of insulin's biological mode of action. Pershadsingh, H. A. and Kurtz, T. W., 1988, Letter to N. ENG. J. Med. 318:383-384 and Pershadsingh, H. A. and McDonald, J. M., 1984, Hormone-Receptor Coupling and the Molecular Mechanism of Insulin Action in the Adipocyte: A Paradigm for Ca.sup.2+ Homeostasis in the Initiation of the Insulin-Induced Metabolic Cascade, Cell Calcium, 5:111-130; and, Klip, A., 1984, Is Intracellular Ca.sup.2+ Involved in Insulin Stimulation of Sugar Transport? Fact and Prejudice, Canad. J. Biochem. Cell. Biol. 62:1228-1236.
High intracellular calcium levels have been associated with hypertension. Sugiyama, T. et al., 1986, The elevation of the cytoplasmic calcium ions in vascular smooth muscle cells in SHR--measurement of the free calcium ions in single living cells by laser microfluorospectrometry, Biochem. Biophys. Res. Comm. 141:340-345.